Abstract

Rheumatoid arthritis (RA) is a progressive autoimmune disease characterized by
synovial membrane hyperplasia, inflammation, and angiogenesis. Hepatocyte growth
factor (HGF) and its receptor, c-Met, are both overexpressed in the RA synovium.
NK4 is an antagonist of HGF which has been shown to inhibit tumor growth,
metastasis, and angiogenesis. In an experimental model of RA, NK4 gene therapy
inhibited joint damage and inflammation in both preventative and therapeutic
models. NK4 treatment therefore represents a possible therapeutic option in
combating RA.

Editorial

Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune disease
characterized by an erosive synovitis. In addition to being an inflammatory
condition, RA is also considered to be a member of the angiogenic family of
diseases. Angiogenesis is growth of new blood vessels from pre-existing blood
vessels. As the disease progresses, the hyperplastic synovial pannus creates a
hypoxic, inflammatory environment that induces angiogenesis. Further vascularization
of the synovial tissue promotes pannus growth and continued infiltration of
inflammatory leukocytes, thus perpetuating the disease.

In the previous issue of Arthritis Research & Therapy, Tsunemi and
colleagues [1] reported on the targeting of hepatocyte growth factor (HGF) by NK4 in the
treatment of RA. HGF is a pleiotropic growth factor that is expressed by mesenchymal
cells and promotes processes such as mitogenesis, differentiation, and angiogenesis
[2]. It mediates these functions via binding to its unique receptor c-Met, a
receptor tyrosine kinase. c-Met is expressed by a variety of cell types, including
endothelial cells (ECs) [3].

We have previously shown that HGF is elevated in the synovial fluid of patients with
RA [4]. More recently, Grandaunet and colleagues [5] found that plasma levels of HGF predict the severity of joint damage in
patients with RA. In the joint, we found that HGF and c-Met are elevated in the
RA
synovial lining compared with normal controls [4]. The report by Tsunemi and colleagues [1] supports these findings and further shows that c-Met is expressed on
fibroblasts, mononuclear cells, and ECs in the RA synovium.

HGF is a heterodimeric protein composed of an ?-chain, which contains four kringle
domains, and a ?-chain [6]. The ?-chain binds c-Met with high affinity, whereas the ?-chain is
responsible for activation of c-Met. In an attempt to inhibit HGF, Date and
colleagues [7] generated a cleavage product of HGF termed NK4, which contains the four
kringle domains of the HGF ?-chain. Therefore, NK4 serves as an antagonist of
HGF
and can bind c-Met with high affinity without activating it.

As described above, one of the primary functions of HGF is to induce angiogenesis
by
binding to c-Met on the surface of ECs. Therefore, it was postulated that NK4
would
act as a competitive inhibitor of HGF, thus inhibiting angiogenesis. Indeed, NK4
has
been shown to inhibit angiogenesis in vitro and in various in vivo
cancer models [6,8,9]. However, in addition to having antagonistic action against HGF, NK4
inhibits angiogenesis induced by vascular endothelial growth factor and basic
fibroblast growth factor in a c-Met-independent fashion [9]. In addition to c-Met, NK4 binds to perlecan, a sulfate proteoglycan that
interacts with the vascular endothelial basement membrane. Sakai and colleagues
[9] found, specifically, that NK4 binds perlecan and prevents proper
fibronectin assembly in the basement membrane, which inhibits several facets of
angiogenesis.

These features of NK4 make it an attractive potential adjunctive therapy in
angiogenic diseases. Over the past decade, numerous studies have been performed
to
assess the efficacy of either a recombinant NK4 protein or NK4 gene expression
vector in many experimental cancer models [3,6]. Collectively, these studies have indicated that NK4 treatment has the
potential to inhibit tumor growth, angiogenesis, and metastasis [3,6]. Much of the preclinical success of NK4 can be attributed to its ability
to inhibit multiple pathways involved in growth and angiogenesis.

RA is driven by inflammation and angiogenesis, and thus much work has been aimed at
identifying and testing potential angiogenesis inhibitors in models of experimental
arthritis [10]. Tsunemi and colleagues [1] have now adopted their approach of studying the antiangiogenic properties
of NK4 in cancer to experimental arthritis. Using an adenovirus vector containing
the NK4 gene, they found that NK4 inhibited the development of ?-glucan-induced
arthritis [1]. NK4 was able to inhibit inflammation, joint swelling, and bone erosion.
However, the authors did not show direct evidence of NK4 inhibiting synovial blood
vessel density. Importantly, they also showed that NK4 gene therapy was effective
when given therapeutically, after the onset of the experimental arthritis [1].

These results are highly encouraging in the application of NK4 as a potential
adjunctive RA therapy. This report, coupled with the high expression levels of
HGF
and c-Met in the RA synovium, makes NK4 treatment an intriguing possibility. In
the
future, it will be of great interest to determine whether these effects of NK4
are
observable in other animal models of RA, as not all facets of RA are represented
in
a singular model of the disease. Moreover, many of the effects of NK4 observed
by
Tsunemi and colleagues [1] are attributed to a reduction in inflammation and inflammatory cytokines.
Therefore, elucidating the anti-inflammatory and antiangiogenic mechanisms of
NK4
will be paramount to transitioning from an interesting candidate to a possible
RA
therapy.